Synthesis of halogenated steroids of the pregnene series



United States Patent Ofi ice 3,364,204 Patented Jan. 16, 1968 3,364,204 SYNTHESIS OF HALOGENATED STEROIDS OF THE PREGNENE SERIES Patrick A. Diassi, Westfield, andJosef. Fried, Princeton, N.J., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 9, 1960, Ser N o. 7,521

5 Claims. (Cl. 260-23955)- wherein the 1,2 position is saturated or dOubIe bonded; Y is hydrogen or the acyl group of a hydrocarbon carboxylic acid, of less than ten carbon atoms; Z is iodo, bromo' or chloro; and X is chloro or fiuoro. Those steroids of the above formula wherein Y is the acyl group of a hydrocarbon carboxylic acid of less than ten carbon atoms, are physiologically active substances which possess progestational activity and thus may be used instead of known progestational agents, such as progesterone, in the treatment of such conditions as habitual or threatened abortion, for which purpose they are administered parenterally in the same manner as progesterone.

The compounds of this invention can be prepared by three different processes which can be represented scheinatically by the following equations:

0 K) V/A/ OH C1 X E 0 VII (IQ-saturated) IV A:--CH2CH2-; X=F XII (1,2-saturated) VIII (1,2-d0uble-b0nded) V A=CH:CH2; X:C1 XIII (l,2-donblebonded) XIV 1.2-satnrated; Z231; X:F XVIII 1,2-saturated; Z:I; XzCl XV -1,2-saturated 2:131; XzCl XIX 1,2-d0uble-bonded; ZzCl; XzCl XVI 1,2-satura-ted; Z=C1; X F XX 1,2-double-bonded; Z Br; N=F XVII 1,2-saturated; ZzCl; X=C1 CH3 CH: CH3 CH3 C=O C=O =0 C=O -OY' --OH "OH ""0 CH:

--z -0Y 0H l 0 CH; /1\l /1\/\/ /1\! /1\I J K L M XXI 1,2-satnrated; Z=Br X=F; YIICHQCO XXXIV 1,2-saturated; N:F XXXVIII 1,2-saturated; X F XXII 1,2-saturated; Z=Br; X=C1; Yz CHaCO XXXV 1,2-satnrated; X=Cl XXXIX 1,2-saturated; X=C1 XXIII 1,2-saturated; 2:01; X:F; Y'zCHaCO XXXVI 1,2-d0uble-bonded X=Cl XL 1,2-doub1e-bonded X CI XXIV 1,2-saturated; ZCl X=Cl; YzcHaCHzcO XXXVII 1,2d0uble-bonded; Xzls XLI 'l,2-double-bonded X F wherein A is a lower alkylene radical, preferably having 65 carboxylic acids, lower cycloalkene carboxylic acids,

1 to 3 carbon atoms in the chain as exemplified by ethylmonocyclic aryl carboxylic acids (e.g., benzoic acid), and ene, propylene-1,3 and propylene-1,2; X is chloro or monocyclic aralkanoic acids (e.g., phenylacetic acid).

fluoro; A is lower alkyl, preferably methyl or ethyl; W In accordance with one method of this invention, 16a, is iodo, bromo 0r chloro; Z is iodo, bromo or chloro; l7a-epoxyprogesterone (I) is diketalized in the 3,20- and Y is the acyl radical of a hydrocarbon carboxylic 70 positions by treatment with a ketalizing agent, such as a acid of less than ten carbon atoms. In all instances Y lower alkanediol (e.g., ethylene glycol and propylene gly- (and Y when an acyl radical) are preferably the acyl col) in an acidic medium, thereby forming the 3,20- radical of such hydrocarbon carboxylic acids as the lower diketals of this invention (Compounds A). The diketal alkanoic acids (e.g., acetic, propionic, n-butyric and is then epoxidized in the 5,6-position by treatment with enanthic acid), lower alkenoic acids, lower cycloalkane 75 an organic peracid, such as perphthalic, perbenzoic and peracetic acid, to yield the 5a,6a; 16a,17m-diepoxides of this invention (Compounds B).

Compounds B are then treated with either boron trifluoride or boron trichloride to selectively open the epoxy group in the 5,6-position thereby yielding the 5a-hydroxy- 6B-halo derivatives (Compounds C) wherein the halogen corresponds to the halogen of the boron trihalide reactant.

Compounds C are then treated with a hydrohalic acid, such as hydrochloric acid, hydrobromic acid and hydroiodic acid, in an organic solvent containing water whereby the l6a,l7e-epoxy ring is opened to yield a 16,8-halo- 17u-hydroxy derivative, wherein the l6-halo group corresponds to the halogen of the hydrohalic acid reactant. Simultaneously, the ketal groups are hydrolyzed off, the steroid is dehydrated thereby introducing a double-bond in the 4,5-position, and the GB-halo group is inverted, thereby yielding Compounds H, wherein the 1,2-position is saturated.

If a 1,2-unsaturated steroid is desired as the final product, Compounds H, saturated in the 1,2-position, can be microbially dehydrogenated in this position by treatment with a microorganism, such as Bacterium cycloxydans in accordance with the method disclosed in US. Patent No. 2,822,318.

Alternatively, compounds of the Formula H may be prepared by converting l6u,17a-epoxyprogesterone (I) to its enol ether (Compounds D) by treatment with a lower alkyl orthoformate (e.g., ethyl orthoformate) in the presence of an acid catalyst. Compounds D are then treated with a chlorinating agent such as an N-chloroamide or N-chloroimide of a hydrocarbon carboxylic acid (e.g., N-chlorsuccinimide and N-chloracetamide) to introduce a chloro radical in the 6B positi0n and reconvert the enol ether to its 3-keto-A -derivative (Compounds E, wherein the 1,2-position is saturated). If a A -pregnadiene is desired, the A pregnene is then 1,2-dehydrogenated microbiologically, as by the use of Bacterium cyclooxydans, as described hereinbefore.

Compounds E, upon treatment with a hydrohalic acid as described hereinbefore then yield the desired compounds of Formula H.

As a third alternative, compounds of the Formula H may be prepared by treating 16a,l7a-epoxypregnenolone (IX) with a halogenating agent in the presence of hydrogen fiuoride. Suitable halogenating agents include the N-iodo, N-brorno and N-chloro amides and irnides of hydrocarbon carboxylic acids, such as N-iodoacetarnide, N-bromacetamide, N-chloracetamide, N-bromosuccinimide and N-chlorosuccinirnide. The process results in the introduction of two dissimilar halo radicals into the steroid nucleus. Into the 6,B-position is introduced a fiuoro radical, whereas in the SwpositiOn is introduced a halo radical, wherein the halo group correspond to that of the halogenating agent, thereby yielding Compounds F, wherein R is hydroxy.

Compounds F, wherein R is hydroxy, are then oxidized by treatment With an oxidizing agent (e.g., chrornic oxide) capable of converting a 3-hydroxyl group to a 3-keto group, thereby yielding compounds of the Formula F, wherein R is keto, which in turn are dehydrohalogenated by heating with a salt of a strong base and a weak acid (e.g., sodium acetate) to yield the corresponding 3-keto- A -derivative (Compounds G, wherein the 1,2-position is saturated). If a 1,2-unsaturated derivative is desired, it is formed by microbiological 1,2-dehydrogenation as described hereinbefore.

Compounds G are then treated with a hydrohalic acid as described hereinbefore to yield compounds of the Formula H.

Compounds H are then converted to the physiologically active 17a-ester derivatives by treatment with an acid halide or acid anhydride, of a hydrocarbon carboxylic acid of less than ten carbon atoms, such as the acyl chlorides or acid anhydrides of the hydrocarbon carboxylic acids of less than ten carbon atoms enumerated hereinbefore, thereby yielding Compounds J.

Aside from their use as physiologically active steroids per se, Compounds I can be converted, by treatment in an acidic aqueous organic medium containing a salt of a strong base and weak acid (e.g., sodium acetate in aqueous acetic acid), to the corresponding 16a-acyloxy- 17e-hydroxy derivative (Compounds K) wherein the acyl group is the same as that originally present in the 17-position.

Compounds K can then be hydrolyzed by treatment with a salt of a strong base and weak acid (e.g., sodium carbonate) in an alcoholic medium (e.g., methanol) to yield the free 160:,17rx-dii1Ydl'OXY derivative (Compounds L), which can then be ketalized in the 16,17-position as by treatment with acetone in an acid medium to yield the corresponding 160:,l7a-3C6t011id68 (Compounds M). These acetonides are physiologically active substances which possess progestational activity and hence may be administered either perorally or parenterally for the treatment of such conditions as habitual or threatened abortion, being formulated for such administration in the usual perorally or parenterally acceptable preparation.

The following examples illustrate the invention (all temperatures being in centigrade). The first seven examples illustrate the first alternative method for preparing the compounds of this invention:

Example l.16a,]7a-ep0xy-A -pregnene-3,20-di0ne 3,20-bis-ethylene ketal (II) A solution of 5.0 g. of 16a,17a-epoxyprogesterone (I) in a mixture of 40 ml. of ethylene glycol and 175 ml. of benzene is refluxed for one hour using a Dean Stark separator for collecting the distilled Water. To this solution is added mg. of p-toluenesulfonic acid and the mixture is refluxed for four hours with stirring. The reaction mixture is cooled and extracted with saturated sodium bicarbonate. The organic phase is then Washed well with Water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuum. Recrystallization of the residue from acetone hexane gives pure 16a,17a-epoXy-A -pregnene-3,20-dione 3,20 bis ethylene ketal.

If propylene glycol is substituted for the ethylene glycol in Example 1, the corresponding 3,20-bis-propylene ketal is obtained as the product.

Example 2.5u,6cc,'1 6a,17u-diep0xypregnane-3,20-di0ne 3,20-bis-ethylene ketal (III) A solution of mg. of 16a,17ot-epoxy-A -pregnene- 3,20-dione 3,20-bis-e'thylene ketal in 10 ml. of chloroform is cooled to 0 and 2.13 ml. of 0.37 N monoperphthalic acid in ether is added. The reaction is left at 0 for 16 hours and then poured into a cold mixture of chloroform and dilute sodium bicarbonate. The chloroform is separated, Washed several times With Water and evaporated to dryness. Fractional crystallization of the residue from acetone gives 5u,6a;16a,17a-diepoxypregnane-3,20-dione 3,20 -bis-ethylene ketal.

Similarly, the 3,20-bis-propylene ketal of 1711- epoxy-A -pregnene-3,ZO-dione yields 5a,6a;16rx,17or-diepoxypregnane-3,20-dione 3,20-bis-propylene ketal.

Example 3 .-6 B-fluoroJ 6 1,1 7 a-epoxy pregnane-S a-ol-3, ZO-dione 3,20-bis-ethylene ketal (IV) To a solution of 3.0 g. of 5oz,6a;16a,17u-diepoxypregnane-3,20-dione 3,20-bis-ethylene ketal in 500 ml. of dry benzene and 500 ml. of dry ether is added 12.5 ml. of freshly distilled boron trifluoride-etherate and the reaction mixture is left at room temperature for three hours. 900 m1. of water is added and the mixture is neutralized with dilute sodium bicarbonate. The organic phase is separated, washed several times with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Crystallization of the residue from methanol gives 7 6B fluoro-16a,17a-epoxypregnane-5a-ol-3,20-dione 3,20- bis-ethylene ketal.

Example 4 .6/5-chl0ro-I 6a,] 7a-ep0xypregnane-5a-0l-3, 20-di0ne 3,20-bis-ethylene ketal (V) Following the procedure of Example 3 but substituting 12.5 ml. of freshly distilled boron trichloride for the boron trifluoride-etherate, 6fl-chloro-16a,l7a-epoxypregnane-5a-ol-3,20-dione 3,20-bis-ethylene ketal is obtained.

To a solution of 100 mg. of 6B-fluoro-16a,l7u-epoxypregnane-Sa-ol-S,20-dione 3,20-bisethylene ketal in 1 ml. of acetic acid, 0.1 ml. of 33% hydrobromic acid in acetic acid is added and the reaction mixture is left at room temperature for two hours. It is then diluted with water, extracted with chloroform and the chloroform extract washed with dilute sodium bicarbonate and Water. The chloroform is evaporated to dryness and the residue crystallized from acetone-hexane to give 6ot-fiuoro-l6fi-bromo- A -pregnane-l7u-ol-3,20-dione.

Example 6 .6 a-chloro-I 6 s-bromo-A -pregnen e-I 7 oc-Ol- 3,20-dine (XV) Following the procedure of Example but substituting 100 mg. of Gfi-chloro-l6a,17ot-epoxypregnane-5a-ol-3,20- dione 3,20-bis-ethylene ketal for the 6 3fiU.OIO-16a,17ot epoxypregnane 5a-ol-3,20-dione 3,20-bis-ethylene ketal, 6a chloro 16fi-bromo-A -pregnene-17a-ol-3,20-dione is obtained.

Following the procedure of Example 5 but substituting 0.1 m1. of concentrated aqueous hydrochloric acid for the hydrobromic acid in acetic acid, 6a-fiuoro-16fi-chloro- A -pregnene-l7a-ol-3,20-dione is obtained.

The following six examples illustrate the second alternative method for preparing the 6a-chloro-compounds of this invention:

Example 8.3-ethoxy-16a,]7a-ep0xy-A -prenadiene- 20-0ne (VI) To a solution of 2.27 g. of 16a,17a-epoxyprogesterone in 22.0 ml. of dioxane is added 0.22 ml. of absolute ethanol and 2.27 ml. of ethyl orthoformate. To this mixture is then added dropwise 1.59 ml. of a solution of 0.5 ml. of sulfuric acid in 10 ml. of dioxane. After minutes at room temperature, the sulfuric acid is neutralized by addition of a drop of pyridine. Water is then added slowly with swirling whereupon the 3-ethoxy-l6a,l7a-epoxy- A -pregnadiene--one crystallizes as long needles. These are filtered, Washed with Water containing a drop of pyridine and dried to give about 2.34 g. of product of the following properties: M.P. about 1l8-120,

[OI]D+14 (chloroform); M113. 240 m (e=18,500); kfjgi 5.86, 6.00, 6.05, 6.15

Analysis.Calcd. for C23H32O3'1/2 C, 75.58; H, 9.10. Found: C, 75.89; H 8.82.

Similarly by substituting 2.2 ml. of methyl orthoformate for the ethyl orthoformate in Example 8, S-methoxy- 16a,17u-epoxy-A -pregnadiene-20-one is produced.

Example 9.6;8-chlor0-I 6a,] 7a-epoxyprogesterone (VII) To a solution of 2.0 g.. of 3-ethoxy-16a,17a-epoxy- A -pregnadiene-20-one in 25 ml. of dioxane, is added dropwise a solution of 742.9 mg. of N-chlorosuccinimide in ZO ml. of dioxane, followed by 15 ml. of a sodium acetate-acetic acid buffer containing 6.6 g. of sodium acetate and 6.6 ml. of acetic acid per 100 ml. of water. After minutes at room temperature, the reaction mixture is diluted with water whereupon crystalline 6p-chloro- 16a,l7a-epoxyprogesterone separates. It is filtered, Washed with water and dried.

6,3 chloro 16u,17a epoxyprogesterone is dehydrogenated in the 1,2-position to 6,8-chloro-16a,17a-epoxy- A -pregnadiene-3,20-dione by means of Bacterium cyclooxydans A.T.C.C. No. 12,673 using the method of Example 1 of U.S. Patent No. 2,822,318 and substituting 500 mg. of 6,6-chloro-16a,17et-expoxyprogesterone for the 11ahydroxyprogesterone of the example.

Example I I .6a,.l 6 3-diehlor0-1 7 whydroxy progesterone (XVII) To a solution of 100 mg. of 6B-Chl0l'O-16oc,17cc-6POXY- progesterone in 1.0 ml. of acetic acid, 0.1 ml. of a solution of concentrated aqueous hydrogen chloride is added and the mixture is left at room temperature for two hours. The solution is then diluted with water and the crystals thus formed are filtered, washed with water and dried. Recrystallization from acetone gives about 20 mg. of 611,165- dichloro-17u-hydroxyprogesterone.

Example 12.6a-Chl0r0-I 6fl-iod0-1 7a-hydr0xyprogesterone (XVIII) Following the procedure of Example 11 but substituting 0.1 ml. of a freshly distilled solution of 50% aqueous hydrogen iodide for the hydrogen chloride in acetic acid, there is obtained 6a-chloro-16fl-iodo-17a-hydroxyprogesterone.

Example 13.--6a,16fi-dichl0r0-A -pregnadiene-1 7oc-Ol- 3,20-di0ne (XIX) Following the procedure of Example 11 but substituting 100 mg. of 6/3-Cl'll0l'0-1606,170t-6P0XY-A -pregnadiene- 3,20-dione for the 6/3-chloro-16a,17a-epoxypr0gesterone, 6a,l6,3 dichloro A -pregnadiene-17a-ol-3,20-dione is obtained.

The following five examples illustrate an alternative method for preparing the 6a-fluoro compounds of this invention:

To a solution of 5.0 g. of 16a,17a-epoxy-A -pregnene- 3fi-ol-20-one (IX) in a mixture of 175 ml. of chloroform and 10.0 ml. of dry tetrahydrofuran contained in a polyethylene bottle and cooled to is added 8.0 ml. (788 mmols.) of hydrogen fluoride with stirring followed by the gradual addition of 2.25 g. of N-bromoacetarnide. After one hour at 80, during which time the solution turns cherry red, the reaction is brought up to 10 and left at this temperature for three hours. The reaction mixture is then poured into a mixture of chloroform (300 ml.) and ice-water (300 ml.) contained in a polyethylene beaker and neutralized with sodium bicarbonate. The chloroform is separated, washed with water and evaporated to dryness. Crystallization of the residue from acetone-hexane gives about 3.5 g. of 5ot-bromo-6fi-fluoro- 16a,l7a-epoxypregnane-3B-ol-20-one of the following properties: M.P. about l197;

[a] 29.4 (chloroform); X123 none; A

To a solution of 2.0 g. of 5u-bromo-6B-fluoro-l6a,17a-

75 epoxypregnane-3 3-ol-20-one in 22 ml. of acetone is added Example 1 6.6,8-fluoro-1 6 a,] 7 lit-epoxyprogesterone (XII) To a solution of 500 mg. of sodium acetate in 45 ml. of methanol is added 500 mg. of Sa-b-I'OIIlO-Gfl-flUOI'O-16a, 17a-epoxypregnane-3,20-dione and the mixture is refluxed for 30 minutes. The solution is then cooled, neutralized with dilute acetic acid and diluted with water whereupon crystalline needles separate. These are filtered, washed with water and dried to give about 300 mg. of 65-fluoro- 16a,Nix-epoxyprogesterone, M.P. about 205-206;

[a] l-59. (chloroform); half, 234 mp (6=9,600); rig 5.85, 5.95, 6.17,.

Analysis.-Calcd. for C H O F: C, 72.80; H, 7.86; F, 5.48. Found: C, 73.05; H, 7.89; F, 5.79.

Similarly, by substituting 5a iodo 6,3fiuOI0-16a,17aepoxypregnane 3,20 dione and 5a-chloro-6p-fluoro-16a, 17cc epoxypregnane 3,20 dione for the 5a-bromo-6 3- fiuoro-16a,l7a-epoxypregnane-3,20-dione in the procedure of Example 16, 6,6-fluoro-16a,Nix-epoxyprogesterone is likewise formed.

6fi-fluoro-l6a,Nix-epoxyprogesterone is dehydrogenated in the 1,2-position to 6B-fluoro-16a,17a-epoxy-A -pregnadiene-3,20-dione by means of Bacterium cyclo-oxya ans A.T.C.C. No. 12,673 using the method of Example 1 of US. Patent No. 2,822,318 and substituting 500 mg. of 6p fluoro 16a,17x epoxyprogesterone for the 110: hydroxyprogesterone of the example.

Example 18.6a-fluoro-16fl-brom0-I7a-hydr0xyprogesterone (XIV) To a suspension of 1.0 g. of 6B-fluoro-16u,17a-epoxyprogesterone in ml. of acetic acid, 1.0 ml. of 33% hydrogen bromide in acetic acid is added and the mixture stirred at room temperature for 30 minutes during which time the compound dissolves. The solution is diluted with water, the resulting crystals filtered, washed with water and then dried. Recrystallization from acetone-hexane gives about 900 mg. of GwflHOrO-l6/3-b1'0II10-17a-1JYGIOXY- progesterone: M.P. about 194-195;

max.

Analysis.-Calcd. for C H 0 BrF(427.35): C, 59.01; H, 6.60; Br, 18.70; F, 4.44. Found: C, 59.14; H, 6.73; Br, 18.72; F, 4.84.

Similarly by substituting an equivalent amount of hydrogen chloride and hydrogen iodide for the hydrogen bromide in the procedure of Example 18, 6a-fluoro-16B- chloro-l7a-hydroxyprogesterone and 6iz-fluoro-l6fi-iodo- 17a-hydroxyprogesterone are formed, respectively.

l. 0 Example 19.-6a-fluor0-16,8-br0m0-A -pregnaa iene-fiaol-3,20-di0ne (XX) Following the procedure of Example 18, but substituting 1.0 g. of 6fi-fiuoro-16a,l7ot-epoxy-A -pregnadiene- 3,20-dione for the 6fi-fiuoro-l6a,Nix-epoxyprogesterone, 6a-fiuoro-16fl-bromo-A -pregnadiene 17oc0l-3,20-dl0116 is obtained.

Example 20.6a-flu0ro-16fi-bromo-1 7 a-acetoxyprogesterone (XXI) To a stirred suspension of 200 mg. of 6oz-11HOIO-l6fibromo-17a-hydroxyprogesterone in 5.0 ml. of acetic anhydride, 0.1 ml. of a solution of 0.1 ml. of 70% perchloric acid in 10 ml. of acetic anhydride is added. The mixture is stirred for 30 minutes during which time the steroid dissolves and the solution darkens. It is then poured onto ice and stirred vigorously until the acetic anhydride is hydrolyzed, and the oil which first separates becomes crystalline. The crystals are filtered, washed with water, dried and then recrystallized from acetone-hexane to give about mg. of 6u-fluoro-16,6-br0mo-17a-acetoxyprogesterone; M.P. about 144-146;

lazin -F706 (chlorof 236 (62147360); A 5.82, 5.92, 6-03,

AJzalysis.-Calcd. for C H O BrF:C, 58.85; H, 6.44; Br, 17.03; E, 4.05. Found: C, 59.26; H, 6.67; Br, 17.06; F, 3.83.

Similarly, by substituting an equivalent amount of 6achloro 16p bromo-17m-hydroxyprogesterone, 60c-fil10f0- 16,8-chloro-l7a-hydroxyprogesterone, 6 x,16/3 dichloro- A -pregnadiene 17cc ol 3,20-dione and 6u-fillOIO-16/3- bromo-A -pregnadiene 17cc ol 3,20-dione for the Gafluoro -16fl bromo 17cc hydroxyprogesterone in the procedure of Example 20, 6a-chloro-16B-bromo-l7wacetoxyprogesterone (XXII), 60c fiuoro-l6fl-chloro-l7a-acetoxyp-rogesterone (XXIII), 6a,16,3-dichloro-17a-acetoxy- A-pregnadiene-3,20-dione (XXVI) and 6a-fiuoro-16flbromo 17cc acetoxy A pregnadiene 3,20 dione (XXVII) are formed, respectively.

Example 21.6a,16fi-clichloro-I7a-propionyloxyprogesterone (XXIV) To a stirred suspension of 200 mg. of 6a,16,8-dichloro- 17a-hydroxyprogesterone in 5.0 ml. of propionic anhydride, 0.1 ml. of a solution of 0.1 ml. of 70% perchloric acid in 10 ml. of propionic anhydride is added. The mixture is stirred for 30 minutes, during which time the steroid dissolves and the solution darkens. It is then poured onto ice and stirred vigorously until the propionic anhydride is hydrolyzed and the oil which first separates becomes crystalline. The crystals are filtered, washed with water, dried and then recrystallized from acetone-hexane to give 6a,16,8-dichloro-17a-propionyloxyprogesterone.

Example 22.6a-chlor0-J6,3-i0d0-17a-lzeptanoyloxy-- progesterone (XXV) To a stirred suspension of 200 mg. of 6a-chloro-16B- iodo-17a-hydroxyprogesterone in 3 ml. of heptanoic anhydride, 0.1 ml. of a solution of 0.1 ml. of 70% perchloric acid in 10 ml. of heptanoic anhydride is added. The mixture is stirred for 30 minutes during which time the steroid dissolves and the solution darkens. It is then poured onto ice and stirred vigorously until the heptanoic anhydride is hydrolyzed and the oil which first separates becomes crystalline. The crystals are filtered, washed with water, dried and then recrystallized from acetone-hexane to give 6a-chloro-1 6p-iodo-17a-heptanoyloxyprogesterone.

Example 23.6a-fluoro-1 6 01,1 7 u-dihydroxy progesterone 16a-acetate (XX VIII A solution of 122 mg. of 6a-fiuoro-16,8-bromo-17aacetoxyprogesterone and 250 mg. of anhydrous sodium acetate in 4 ml. of acetic acid is refluxed for one hour.

Example 24.-6u-flu0r0-1 6a,] 7u-dihydr0xy progesterone (X XX 1 V) To a solution of 100 mg. of 6a-fiuoro-16a,17a-dihydroxyprogesterone 16a-acetate in 4.5 ml. of methanol is added under a blanket of nitrogen 0.45 ml. of potassium carbonate. After 45 minutes at room temperature, the solution is neutralized with 10% acetic acid and diluted with water whereupon long needles separate. These are filtered off, washed with water, dried and recrystallized from methanol to give about 34 mg. of 6e-fiuoro-16a,17adihydroxyprogesterone: M.P. about 213-214";

[a] +8l.5 (chloroform); 7\ 236 m (e=16,100);

An-alysis.-Calcd. for C H O F (364.44): C, 69.21; H, 8.02; F, 5.20. Found: C, 69.19; H, 8.10; F, 5.02.

Similarly, by substituting an equivalent amount of 60achloro 16a,17a dihydroxyprogesterone 16u-acetate, 60cchloro-n -pregnadiene-16a,17a-diol-3,20-dione 16a-acetate and 6a-fiuoro-A -pregnadiene16a,17a-diol-3,2O-dione 16a-acetate for the 6a-fiuoro 16a,l7a-dihydroxyprogesterone-16a-acetate in the procedure of Example 24, 60cchloro-16a,17a-dihydroxyprogesterone (XXXV), 6e-chloro-A -pregnadiene-16a,17u-diol-3,20 dione (XXXVI), and 6a-fiuoro-A -pregnadiene-16a,17u-di0l 3,20 dione (XXXVII) are obtained, respectively.

Example 25.6u-flu0r0-16a,]7a-dihydroxyprogesterone 16,17-acez0nide (XXXVHI) To a solution of 0.01 ml. of 70% perchloric acid in 2.0 ml. of acetone is added 17.5 mg. of 6a-fiuoro-16a,17a-dihydroxyprogresterone and the solution is stirred at room temperature for one hour. The solution is then neutralized with dilute sodium bicarbonate and on dilution with water the crystalline 6u-fluoro-16a,17a-dihydroxyprogesterone 16,17-acetonide separates as long needles. These are filtered, washed with water and dried to give about 13.8 mg. of product: M.P. about 252253;

Similarly, by substituting an equivalent amount of 60achloro-16u,17a-dihydroxyprogesterone, 6a chloro A pregnadiene-16a,17a-diol-3,20-dione and 6a fluoro-A pregnadiene-l6u,17u-di0l-3,20-dione for the 6a-fiuoro-16e, 17u-dihydroxyprogesterone in the procedure of Example 25, 6oLChlOrO-16cc,17a dihydroxyprogesterone 16,17-acetonide (XXXIX), 6a-chloro-A :*-pregnadiene l6a,l7ot diol-3,20-dione 16,17-acetonide (XL), and 6ufiuoro-A pregnadiene-16a,17u diol-3,20-dione 16,17 acetonide (XLI) are formed respectively.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. 5a,6a; 16a,l7a-diepoxypregnane-3,20-dione 3,,20-bis- (lower alkylene) ketal.

2. 6/3-halo-16a,17a-ep0Xypregnane-5a-ol-3,20-dione 3, ZO-bis-(lower alkylene) ketal, wherein the halogen has an atomic number less than eighteen.

3. 5a-halo-6fi-fluoro-16a,17a-epoXypregnane-3B 01-20- one, wherein the halogen has an atomic number greater than ten.

4. A process for preparing a steroid of the general formula References Cited UNITED STATES PATENTS 8/1954 Julian et al. 260-23955 2,816,108 12/1957 Julian et al. 260-39747 2,838,528 6/1958 Campbell et al. 260-397.3 2,933,492 4/1960 Poos et al 260239.55 2,925,415 2/1960 Loken 260-23955 2,8 37,464 6/1958 Nobile 5l 3,067,213 12/1962 Ringold et al 260-3974 OTHER REFERENCES Fieser et al.: Steroids (1959) pp. 202, 288 and 325.

ELBERT L. ROBERTS, Primary Examiner.

L. H. GASTON, M. LIEBMAN, L. GOTTS, Examiners.

M. L. WILLIAMS, G. E. LANDE, Assistant Examiners. 

1. 5A,6A; 16A, 17 A-DIEPOXYPREGNANE 3,20-DIONE 3,20-BIS(LOWER ALKYLENE) KETAL. 